The use of transgenic animals is a powerful and informative approach that has been successfully undertaken by Core B in previous cycles to study neurodegenerative diseases. Core B will provide Projects 1-4 with appropriately genotyped and aged mouse models of endosomal-autophagic-lysosomal system abnormalities observed in Alzheimer's disease (AD) and Down's syndrome (DS). Core B will also serve to identify novel animal models with these pathologies, and to generate novel crosses between these models, and either transgenic or knockout models that carry or lack genes expected to affect AD-related pathologies. Endosomal abnormalities are the earliest known pathology in AD, preceding AB deposition and, in human DS, can be detected in neurons even before birth. As a model of endosomal pathology we are using the Ts2 trisomic mouse, which we have identified as a model with pathologies similar to Ts65Dn mice yet with important breeding and transmission advantages. Among models used to examine endosomal and autophagic-lysosomal system pathologies are transgenic mice expressing human rab5, XI la, mutant presenilin 1, and knockout mice for presenilin 1. Models of either B-amyloidosis and amyloid p precursor protein (APP) overexpression or knockout are used to examine the effect of APP and APP metabolites on endocytosis and lysosomal system function. Additionally, in order to identify protective effects of cystatin C, which the core leader has shown to affect disease processes, mouse models with endosomal and autophagic-lysosomal system pathologies will be crossed with either transgenic or knockout mice for cystatin C. The Core Leader has extensive experience managing a large mouse colony with complex breeding schemes, and will be able to coordinate animal breeding, genotyping, and delivery to Projects 1-4.